title: Occurrence, distribution, dereplication and efficient discovery of thiazolyl peptides by sensitive-resistant pair screening.
abstract: Natural products have been major sources of antibacterial agents and remain very promising. Frequent rediscoveries of known compounds hampers progress of new discoveries and demands development and utilization of new methods for rapid biological and chemical dereplication. This paper describes an efficient approach for discovery of new thiazolyl peptides by sensitive-resistant pair screening and dereplication in a time and cost-effective manner at industrial scale. A highly effective library-based dereplication of thiazolyl peptides by high resolution fourier transform liquid chromatography mass spectrometry (HRFTLCMS) has been developed, which can detect and dereplicate very low levels of thiazolyl peptides particularly when combined with miniaturized high-throughput 96-well solid-phase extraction separation, and as well can be automated. Combination of sensitive (susceptible)-resistant pair screening, diversified screening collection and miniaturized high-throughput SPE and HRFTLCMS techniques were applied for discovery of new thiazolyl peptides. The combined approach allowed for identification of over 24 thiazolyl peptides represented by three of the five structural subgroups, including three novel compounds. In addition, it is possible for the first time to mechanistically group three structural subgroups of over 24 thiazolyl peptides. Furthermore, these studies helped to understand natural frequency of distribution of these compounds and helped in discovery of new producing strains of many thiazolyl compounds.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Chaowei
authors.initials: C
authors.lastname: Zhang
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.forename: John
authors.initials: J
authors.lastname: Ondeyka
authors.forename: Prakash
authors.initials: P
authors.lastname: Masurekar
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goetz
authors.forename: Jose Rubén
authors.initials: JR
authors.lastname: Tormo
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Jesús
authors.initials: J
authors.lastname: Martín
authors.forename: Ignacio
authors.initials: I
authors.lastname: González
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
mesh_terms: D039903:Actinobacteria / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D024881:Drug Resistance, Bacterial; D005583:Fourier Analysis; D057166:High-Throughput Screening Assays / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D008826:Microbial Sensitivity Tests / Q000379:methods; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D010455:Peptides; D010456:Peptides, Cyclic; D013844:Thiazoles; C525268:thiazomycin